The pathogenesis of neurodegenerative diseases remains obscure. The hallmark of these diverse disorders of the aging brain is selective cell vulnerability in disease-specific patterns many decades after the birth of these long-lived neuronal subtypes. The standard paradigm for investigating pathological brain aging and neurodegeneration has traditionally focused on defining the biological processes and pathways mediating neuronal dysfunction and death during adult life and has considered these disorders as discrete pathological entities rather than as a continuum of a final common pathogenic process. In contrast to the standard paradigm, we hypothesize that neurodegenerative diseases represent a novel class of fundamental disorders of neural development in which subtle impairments in the regional program of stem cell-mediated neurogenesis create selective neuronal and neural network vulnerabilities to a spectrum of late-life stressors. Consistent with our hypothesis, our preliminary observations of complementary profiles of developmental stem cell-mediated impairments in mouse knock-in models of Huntington's and Alzheimer's diseases support the possibility of seminal pathogenic associations between abnormalities in the birth and the death of the vulnerable neuronal subtypes. Therefore, our Specific Aim is to establish causal links between the early developmental impairments and the occurrence of the clinical, pathologic and neurophysiologic hallmarks of the late- onset neurodegenerative process in a well-characterized disease model. As a proof of concept, we will employ Huntington's disease mouse models to determine whether the early developmental impairments are directly responsible for the disease by ablating or inducing expression of the mutant gene both before and after development and assessing the consequences of the gene manipulations for evolution of the characteristic profiles of selective cell vulnerability, dysfunction and neurodegeneration. Verification of our hypothesis will provide compelling experimental evidence that Huntington's disease may represent a fundamental new class of developmental disorders with direct implications for understanding the pathogenesis of other neurodegenerative diseases. Fulfilling the objectives of this unconventional hypothesis would address one of the most vexing conceptual problems in the biomedical sciences that have prevented progress in early diagnosis, treatment and prevention within this field: what is the underlying cause of the invariant regional cellular vulnerabilities in neurodegenerative diseases. This proposal is particularly well suited to the EUREKA mechanism because of its conceptual novelty in addressing a particularly difficult biomedical problem of exceptionally broad scientific as well as public health relevance. Moreover, the unconventional focus on developmental mechanisms mediating diseases of the aging brain and associated co-morbidities affecting multiple organ systems will create important new cross-disciplinary synergies germane to the objectives of multiple NIH Institutes.